CN1538952A - Protected 3,5-dihydroxy-2, 2-dimethyl-valeroamides for synthesis of epothilone and derivatives and method for production and use thereof - Google Patents
Protected 3,5-dihydroxy-2, 2-dimethyl-valeroamides for synthesis of epothilone and derivatives and method for production and use thereof Download PDFInfo
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- CN1538952A CN1538952A CNA028152379A CN02815237A CN1538952A CN 1538952 A CN1538952 A CN 1538952A CN A028152379 A CNA028152379 A CN A028152379A CN 02815237 A CN02815237 A CN 02815237A CN 1538952 A CN1538952 A CN 1538952A
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- China
- Prior art keywords
- benzyl
- compound
- group
- dimethyl
- general formula
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- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 229930013356 epothilone Natural products 0.000 title abstract 3
- ZYRUAVNMUFDGQT-UHFFFAOYSA-N 3,5-dihydroxy-2,2-dimethylpentanamide Chemical class NC(=O)C(C)(C)C(O)CCO ZYRUAVNMUFDGQT-UHFFFAOYSA-N 0.000 title abstract 2
- 150000003883 epothilone derivatives Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 119
- 238000000034 method Methods 0.000 claims abstract description 53
- 150000001408 amides Chemical class 0.000 claims description 50
- 238000002360 preparation method Methods 0.000 claims description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Natural products CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 31
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 30
- -1 TIP Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000006239 protecting group Chemical group 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 claims description 12
- 150000002576 ketones Chemical class 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- QGYNXQMBZVRCEO-YFKPBYRVSA-N (3S)-3,5-dihydroxy-2,2-dimethylpentanoic acid Chemical compound O[C@H](C(C(=O)O)(C)C)CCO QGYNXQMBZVRCEO-YFKPBYRVSA-N 0.000 claims description 9
- 229930189413 Esperamicin Natural products 0.000 claims description 9
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical compound C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 claims description 9
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 8
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims description 8
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 8
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims description 8
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000000468 ketone group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 238000007127 saponification reaction Methods 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 239000004367 Lipase Substances 0.000 claims description 2
- 102000004882 Lipase Human genes 0.000 claims description 2
- 108090001060 Lipase Proteins 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 230000002255 enzymatic effect Effects 0.000 claims description 2
- 238000006911 enzymatic reaction Methods 0.000 claims description 2
- 235000019421 lipase Nutrition 0.000 claims description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims 7
- 241000349731 Afzelia bipindensis Species 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- QBZXOWQOWPHHRA-UHFFFAOYSA-N lithium;ethane Chemical compound [Li+].[CH2-]C QBZXOWQOWPHHRA-UHFFFAOYSA-N 0.000 claims 1
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 4
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 abstract 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 36
- 238000004458 analytical method Methods 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 238000007738 vacuum evaporation Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229940005605 valeric acid Drugs 0.000 description 6
- 238000005575 aldol reaction Methods 0.000 description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000013067 intermediate product Substances 0.000 description 5
- RSLOAZZCRPXMSD-UHFFFAOYSA-N prop-1-enylsilane Chemical group CC=C[SiH3] RSLOAZZCRPXMSD-UHFFFAOYSA-N 0.000 description 5
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000005882 aldol condensation reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- DSSYKIVIOFKYAU-OIBJUYFYSA-N (S)-camphor Chemical compound C1C[C@]2(C)C(=O)C[C@H]1C2(C)C DSSYKIVIOFKYAU-OIBJUYFYSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229960003328 benzoyl peroxide Drugs 0.000 description 2
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 2
- RGVBVVVFSXWUIM-UHFFFAOYSA-M bromo(dimethyl)sulfanium;bromide Chemical compound [Br-].C[S+](C)Br RGVBVVVFSXWUIM-UHFFFAOYSA-M 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 2
- 229960000380 propiolactone Drugs 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 229940075963 (-)- camphor Drugs 0.000 description 1
- YSTPAHQEHQSRJD-SECBINFHSA-N (-)-piperitone Chemical compound CC(C)[C@H]1CCC(C)=CC1=O YSTPAHQEHQSRJD-SECBINFHSA-N 0.000 description 1
- 229930006950 (-)-piperitone Natural products 0.000 description 1
- JRHWHSJDIILJAT-UHFFFAOYSA-N 2-hydroxypentanoic acid Chemical compound CCCC(O)C(O)=O JRHWHSJDIILJAT-UHFFFAOYSA-N 0.000 description 1
- XJGNRXDOYOEFKR-UHFFFAOYSA-N 3-phenylmethoxypropanoyl chloride Chemical compound ClC(=O)CCOCC1=CC=CC=C1 XJGNRXDOYOEFKR-UHFFFAOYSA-N 0.000 description 1
- OQRKBZZNEZCRGO-UHFFFAOYSA-N 5-ethanethioyl-3-methyl-1,3-oxazolidin-2-id-4-one Chemical class CN1[CH-]OC(C1=O)C(C)=S OQRKBZZNEZCRGO-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- JEKXJMDUMGMVCJ-UHFFFAOYSA-N [Li]CCC=C Chemical compound [Li]CCC=C JEKXJMDUMGMVCJ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- LDDQLRUQCUTJBB-UHFFFAOYSA-N ammonium fluoride Chemical compound [NH4+].[F-] LDDQLRUQCUTJBB-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000004718 beta keto acids Chemical class 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- OSXYHAQZDCICNX-UHFFFAOYSA-N dichloro(diphenyl)silane Chemical compound C=1C=CC=CC=1[Si](Cl)(Cl)C1=CC=CC=C1 OSXYHAQZDCICNX-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940059936 lithium bromide Drugs 0.000 description 1
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Inorganic materials [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- YTJXGDYAEOTOCG-UHFFFAOYSA-N lithium;di(propan-2-yl)azanide;oxolane Chemical compound [Li+].C1CCOC1.CC(C)[N-]C(C)C YTJXGDYAEOTOCG-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 230000007483 microbial process Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NBBJYMSMWIIQGU-UHFFFAOYSA-N propionic aldehyde Natural products CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
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Abstract
The invention relates to new protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and process for the production and the use of the new compounds for the production of epothilones or epothilone derivatives.
Description
Background technology
The theme that the present invention relates in claims, characterize, promptly, new intermediate product and its production and application.The method for preparing new intermediate product is begun by the initiator of economy, produces the intermediate product of high antimer purity, high chemical purity with good productive rate, and can carry out plant-scale preparation.
Background technology
The present invention is used for the esperamicin of natural and synthesis modification or derivative synthetic structure piece A.Esperamicin is 16 yuan of macrocylc compound, is to separate in the culture by Myxobacterium SorangiumCellosum, and is that a class is through testing and find the representative of and very promising antitumor drug effective to multiple cancerous cell line.Its synthetic review article is seen people such as J.Muler, J.Org.Chem.2000,65,7456-7467.
In the literature, except that natural esperamicin, disclose multiple synthetic esperamicin derivatives, they mainly are to change in group M and T.Under most situation, M represents heterocyclic group.Synthetic all use of the major part of natural esperamicin and synthetic esperamicin derivatives makes up the piece Segment A, and it represents the carbon atom C in the macrolide
5-C
10Make up among the piece A (as follows) C at this
1Be the C of macrolide
5, and C
6Be the C in the macrolide
10, or the like.
At this, T represents C
1-4Alkyl or alkenyl, and Sg
1And Sg
2Represent protecting group well known to those skilled in the art, as the TBDMS group.
The possible preparation method who makes up piece A has for example been described in WO 00/58254.Disclose the synthetic of beta-keto esters in the document, this keto esters can be converted into by a plurality of steps and make up piece A.According to the method for Noyori, can introduce chirality by the asymmetric hydrogenation beta-keto esters:
In this regard, ester group is converted into ketone group can only be undertaken by a plurality of steps.In the case, behind protection 1-hydroxyl and 3-hydroxyl, reduction ester group (C-5 atom) forms alcohol, is oxidized to aldehyde then, carries out the Grignard addition of alkyl with alkyl magnesium and alkyl lithium compounds, produces secondary alcohol, then again this alcohol is carried out oxidation.For obtaining ketone, need 8 steps altogether from ester.The direct reaction of ester is not optionally, because the middle product that produces is further reacted.Following route map has shown whole synthesis path:
People such as B.Paniker have described the method that makes up piece A that produces at Tetrahedron 200,56 among the 78-59-7868.It is described to, and aldol and the reaction of chirality composition produce the lower reaction of selectivity.Described detour, in multistep processes,, improved non-enantiomer selectivity ground and synthesized chirality C3 atom by the boron enolate by N-methyl ethanethioyl-oxazolidones.For realizing operable non-enantiomer selectivity, it is necessary that methylthio group replaces, and the thioether that ruptures after aldol reaction.
In addition, and prior art (R.E.Taylor, Y.Chen, Org.Lett. (2001), 3 (14), 2221-2224) a kind of method is also disclosed, wherein use phenylester.The productive rate that can reach is 77% in the case.(Chem.Comm.2001,1057-1059) among the embodiment of Miao Shuing, productive rate reaches 67% at A.Fuerstner.The productive rate of these methods of the prior art is starkly lower than productive rate of the present invention.
At J.Org.Chem.2000,65, among the 7456-7467, further described the asymmetric synthesis of beta-keto esters, wherein asymmetrical form embodiment is carried out with aldol reaction.In the method, the D-Ts-Xie Ansuan is used as catalyzer, and it can be by the amino acid D-Xie Ansuan preparation of costliness.This method produces 90% ee value.Another method in this respect is described in R.E.Taylor, Y.Chen, and Org.Lett. (2001), 3 (14), among the 2221-2224, it also is asymmetric aldol reaction, productive rate is 71%.
Another method of the structure piece A-ethyl ketone of preparation double T BDMS protection finally is described in the following document: Nicolaou, Chem.Eur.J.2000,6,2783-2800.
Summary of the invention
An object of the present invention is to prepare can widely used general formula I initial intermediate compound and the optical purity enantiomorph of general formula I a, Ib, use the complete synthesis structure piece Segment A of esperamicin with preparation:
R wherein
1, R
2Can be identical or different; and represent pure protecting group well known by persons skilled in the art independently of each other; as benzyl, 4-methoxy-benzyl, 3, if 4-dimethoxy-benzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl group, trityl are perhaps R
1And R
2Bridge joint is then represented the ketone acetal protecting group together:
U wherein
1, U
2Represent alkyl, phenyl, the tertiary butyl, U represents C
1-6Alkyl, Y represents group-NA1A2, and wherein A1 and A2 represent the C1-6 alkyl independently of each other, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
For this reason, the compound of general formula I is following reacts:
Compound of Formula I and enantiomorph Ia, Ib form the reaction of ketone AK and carry out with lithium methide or methyl grignard compound according to standard method well known by persons skilled in the art, obtain ketone with the water-bearing media aftertreatment.Use alkyl halide or the alkenyl halide of formula T-Hal (Hal=Cl, Br, I or toluenesulphonic acids base, methylsulfonic acid base, trifluoromethanesulfonic acid base (triflate) etc.) to carry out alkylated reaction subsequently, produce and make up the piece Segment A by means of alkali.
But compd A also can directly obtain by the following method: the acid amides of general formula I direct and organometallic compound such as lithium compound Li-CH
2-T reaction is carried out aftertreatment with moisture form then.
In principle, above-mentioned reaction can successfully be carried out and make structure piece A with high yield.
Therefore, still need a kind of plant-scale method, it allows preparation can widely usedly be used for preparing the intermediate compound of the complete synthesis structure piece A of esperamicin.
The high yield in being converted into the reaction that makes up piece A, compound of Formula I can relatively easily be made by relatively inexpensive initiator.In addition, opposite with known ester and ketone in the document, compound according to the present invention is stable between the shelf lives, and great majority are crystal, and can carry out pure system by crystallization.In this way, can obtain high chemistry and optical yields (e.e.＞98%).
Method I (by total preparation method of aldol reaction)
If a) R
1And R
2Represent the ketone acetal protecting group, perhaps R
1=R
2, then the compound of general formula I can be prepared according to protecting group chemical process well known by persons skilled in the art by the compound of general formula I I:
Wherein Y is identical with above definition,
For example, their preparation and fracture method be referring to following document: P.J.Kocienski, ProtectingGroups, Georg Thieme Verlag Stuttgart, New York, 1994; And HoubenWeyl, the 4th edition, VI/1b volume, the 737th page, Thieme Stuttgart 1984.
B) if R
1And R
2Do not represent the ketone acetal protecting group, and be identical or different, then the compound of general formula I can be directly directly prepared by the compound of general formula III, wherein introduces protecting group R by known method in the document
2(people such as J.Mulzer, J.Org.Chem.2000,65,7456-7467).
The compound of general formula I I can be by the compound of general formula III:
Wherein Y is identical with above definition, and R
1Represent protecting group as defined above, wherein according to the pure protecting group method of fracture well known by persons skilled in the art (P.J.Kocienski, Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994; And Houben Weyl, the 4th edition, VI/1b volume, the 737th page, Thieme Stuttgart 1984) fracture protecting group R
1
The compound of general formula III can be by the compound of general formula I V
By with the compound of formula V
Wherein Y and R
1Identical with above definition; and L represents the silyl protecting group; as TBDMS, TMS, TES, TIP, TBDPS; according to mode (C.H.Heathcock well known by persons skilled in the art; Modern SynthesisMethods; 1992 (Hrsg.R.Scheffold, p.1-102) VHCA BASEL 1992 prepares by aldol reaction.
Yet the preparation of the compound of general formula I V is known for those skilled in the art:
R1＝THP，JOC，1984，49，2301-2309
The R1=benzyl, J.Chem.Soc.Perk.Trans 1,2000,2429-2454
R1＝TBDMS，JOC，2000，65，7456-7467
The synthetic of formula V compound is new, and as be shown in the examples carrying out.
Method II (the opticity intermediate product of preparation general formula I a)
Optically-active compound for preparation general formula I a:
The preparation method is similar to the step described in the method I.The compound for preparing general formula I a by the optically-active intermediate product of general formula I Ia and IIIa.
Optically-active precursor compound by general formula III a like the compounds of general formula I Ia prepares:
The optically-active compound of general formula III a can followingly make:
1, mainly by the SMB technology: people such as A.Seidel-Morgenstern, Chromat.A.1998,827/2,175-191, the separating chiral general formula III racemic compound (document: G.Roussel in mutually, P.Piras, Chirabase, Pure and Applied Chemistry, 1993,65,235-244).
2, initial by the racemic alcohol of general formula III, prepare the ester of general formula VI according to esterification process well known by persons skilled in the art:
R wherein
3Represent C
1-6Alkyl or allyl group, phenyl or benzyl.
The ester of gained carries out saponification with enzymatic method or microbial process enantio-selectivity ground.The alcohol of gained and used ester have tangible difference on their Rf value, therefore for example can easily separate this two kinds of materials by column chromatography.
3, by aldol condensation by the chiral catalyst mediation, use the chirality aldol catalyzer of catalytic amount or stoichiometry, make the compound reaction of general formula I V and V:
Document: referring to for example J.Org.Chem.2000,65,7456-7467.
4, the ketone according to method known to those skilled in the art mutual-through type VII carries out chiral reduction:
Document: people such as Noyori, J.Am.Chem.Soc.1987,109,5850; People such as Noyori, J.Am.Chem.Soc.1988,110,629; R.C.Larock, Comprehensive OrganicTransformations, VCH Publishers New York 1989, ISBN 0-89573-710-8,540-548 page or leaf.
Wherein Y and R
1But, the compound of the compound of general formula VII compound through type V as defined above and general formula VIII prepares for reacting:
Wherein Nu represents leavings group, as Cl, Br, imidazoles ,-OPh ,-O-C
6H
4NO
2,-O-C
1-4Alkyl etc.
This reaction is carried out according to mode well known by persons skilled in the art.Document: Ann.1962,655,90; R.C.Larock, Comprehensive Organic Transformations, VCHPublishers New York 1989, ISBN 0-89573-710-8,658-702 page or leaf.
The preparation of general formula VIII compound is described in the following document: J.Med.Chem.1999,706-721.
In some cases, make by oxidation style well known by persons skilled in the art (for example Swern oxidation, PDC, PCC etc.), be proved to be favourable if the compound of general formula VII is a racemic alcohol by general formula I I.
In some cases, if the compound of the compound of general formula V and propiolactone reaction formation formula IX is proved to be favourable:
The compound of formula IX can be according to method known to those skilled in the art by introducing the compound (P.J.Kocienski that protecting group is converted into general formula VII easily, Protecting Groups, Georg Thieme Verlag Stuttgart, New York, 1994; And Houben Weyl, the 4th edition, VI/1b volume, the 737th page, Thieme Stuttgart 1984).
But, initial by the compound of formula IX, with chemistry or micro-biological process (for example according to JOC 1985,50,127/J.Chem.Soc., Chem.Commun.1987,1368) chiral reduction keto compounds, can make the compound of general formula I Ia:
Method III
The compound of general formula I a
Also can make (seeing the document that is used to introduce protecting group cited above) by the compound of general formula X according to the method that is used to introduce pure protecting group well known by persons skilled in the art.
The compound of general formula X can be by the compound of general formula X I
R wherein
4Represent methylidene, ethyl or benzyl, according to method known to those skilled in the art (R.C.Larock, Comprehensive OrganicTransformations, VCH Publishers New York 1989, ISBN 0-89573-710-8, the 549-551 page or leaf) by also preparation originally of ester.
The compound of general formula X I can be by the compound of general formula X II
R wherein
4Represent C
1-6Alkyl, methyl, ethyl, the tertiary butyl, phenyl or benzyl pass through to introduce protecting group R according to method known to those skilled in the art
2Prepare (seeing above document).
The compound of general formula X II can be made by chiral reduction (chemistry or enzymatic) method by the beta-keto esters of general formula X III:
Document: R.C.Larock, Comprehensive Organic Transformations, VCHPublishers New York 1989, ISBN 0-89573-710-8,540-547 page or leaf.
The compound of general formula X III can prepare by the compound of general formula X IV and the reaction of formula V compound:
The compound of general formula X IV is known in the literature.The compound of general formula V is new, and its preparation method can be with reference to above document and embodiment.
Perhaps the reaction of the compound that the compound of general formula X III can be by general formula X IIIa and XIIIb prepares:
At this, Nu is leavings group as defined above, and Q represents hydrogen atom and COOH group.If Q is a hydrogen atom, then XIIIa removes proton with organic bases such as LDA, then according to method known to those skilled in the art and the reaction of activatory acid derivative.
If Q equals COOH, then according to for example at J.Am.Chem.Soc.1999,121,7050-7062/Synth.Commun.1997,27, the propanedioic acid half ester condensation method of describing among the 3227-3234 is synthesized.
The compound of general formula X IIIa can commercially availablely obtain (for example Aldrich).
The compound of general formula X IIIb can prepare according to the method for describing in the following document: R.C.Larock, Comprehensive Organic Transformations, VCH Publishers New York 1989, ISBN 0-89573-710-8,963-964 page or leaf.
In some cases, when the glycol of synthetic general formula I Ia,
Direct compound by general formula X II,
According to aforesaid method reduction ester group, be proved to be favourable.
The racemic diol of general formula I I also can prepare as initiator by the beta-keto esters that uses general formula X III according to the method that routine is used for ester reduction and ketone:
Method IV
In some cases, be the optically-active glycol of preparation general formula I Ia, advantageously the diastereomer ketone acetal of mutual-through type XIVa and XIVb carries out chromatographic separation or crystallization:
Wherein A represents the group of opticity ketone, and for example (-) piperitone, (-) camphor etc. remove the ketone acetal group according to protecting group chemical process well known by persons skilled in the art then.
The diastereomer 1 of general formula X IVa and XIVb, 3-glycol-ketone acetal can be prepared as follows: the racemic diol of general formula I I is according to known method and chiral ketone reaction in the document.Document: people such as T.Harada, J.Org.Chem.1992,57,1412-1421.
Certainly, the corresponding enantiomeric compounds of general formula I b also can use mirror image catalyzer or other enzyme system to prepare.
According to Mitsunobu (document: Mitsunobu, Synthesis 1981, method 1-28) also can obtain the corresponding enantiomorph of the intermediate of general formula III b by the conversion of hydroxyl:
For the protecting group R that uses in synthetic
1And R
2, benzyl and TBDMS group are preferred.If R
1, R
2Represent the ketone acetal protecting group, then-(C (CH
3)
2)-be is particularly preferred.
Group Y preferably represents following group:
But be preferably dimethylamino especially.
In different preparation methods, following part steps is particularly preferred for preparation achirality precursor compound.
1, the compound for preparing general formula VII by the intermediate compound of general formula V and VIII
L is TMS, R1=benzyl, Nu=Cl, Y=dimethylamino
2, by the compound of the compound general formula X III of general formula V and XIV
L is TMS, R4=ethyl, Nu=Cl, Y=dimethylamino
3, the compound for preparing general formula VII by aldol condensation and oxidizing reaction subsequently
L is TMS, R1=benzyl, Nu=Cl, Y=dimethylamino
4, the compound (wherein Y=dimethylamino) of preparation general formula I X
Be preparation chiral precurser compound, following part steps is particularly preferred.
1, carries out the chirality aldol condensation with chiral catalyst
2, by means of the acetic ester enantio-selectivity saponification of enzyme
3, the chiral reduction of beta-keto acid amides (Noyori type)
4, with reduction reaction subsequently beta-keto esters is carried out chiral reduction
The preparation of The compounds of this invention is preferably carried out according to following steps.
1, preparation acetone acetal
2, the compound of preparation double T BDMS protection
Embodiment
To more obvious according to compound of the present invention and preparation method thereof by the description of following examples.
Embodiment 1a
1-dimethylamino-2-methyl isophthalic acid-trimethyl silyl-propylene
Under-35 ℃ and inert atmosphere, in the solution of 0.43mol diisopropylamine in 300ml THF, drip the butyllithium of 294ml (0.45ml).Then under 0 ℃, add the N of 50g (0.434mol), N-dimethyl-2 Methylpropionic acid acid amides, and under this temperature, stirred 30 minutes.Under-35 ℃, add the trimethylsilyl chloride of 60.3ml (0.47mol) then, and continue to stir 2 hours.In rotatory evaporator, distill solvent.Residue vacuum distilling under 65-69 ℃/30mbar.
1H-NMR(300MHz，CDCl
3，25℃，TMS)，δ＝0.2(s，9H)，1.53(s，3H)，1.63(s，3H)，2.5(s，6H)
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?57.70 | ?11.30 |
| Measured value | ?58.00 | ?11.40 |
Embodiment 1b
Racemize N, the N-dimethyl-(5-benzyloxy-2, and 2-dimethyl-3 (R, S)-hydroxyl-valeric acid) acid amides
In the THF of 500ml, stir title compound 1-dimethylamino-2-methyl isophthalic acid-trimethyl silyl-propylene of 68.8g (0.367mol) embodiment 1a, the benzyloxy propionic aldehyde of 67g (0.4mol) and the ZnCl of 5.56g
2Totally 1 hour.Add the NH of 13.88g
4The methyl alcohol of F and 300ml at room temperature stirred 18 hours then.Distillation removes and desolvates, residue 200ml ethyl acetate extraction, and organic phase is washed with 10% citric acid solution.After carry out chromatographically pure system with ethyl acetate/hexane as eluent on the silica gel, obtain the product (theoretical value 60%) of 60.8g.
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?68.79 | ?9.02 |
| Measured value | ?68.80 | ?9.00 |
Embodiment 1c
N, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3-oxygen base-valeric acid) acid amides
Oxalyl chloride with 2.47g in the 25ml methylene dichloride is cooled to-60 ℃, to wherein adding the solution of 4.4ml DMSO in the 10ml methylene dichloride, continue to stir 15 minutes, to the title compound N that wherein adds 7.26g embodiment 1b, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (R, S)-hydroxyl-valeric acid) solution of acid amides in the 20ml methylene dichloride, continue to stir 30 minutes.Add the triethylamine of 8.7ml, restir 30 minutes is warmed to-20 ℃ simultaneously.Water with 25ml is hydrolyzed, and separates organic phase.Behind the evaporating solvent, obtain the product of 7.18g.After carry out chromatographically pure system, obtain the product (theoretical value 50%) of 3.6g and the educt of 1.36g.
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?69.29 | ?8.36 |
| Measured value | ?69.40 | ?8.50 |
Embodiment 1d
N, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (S)-hydroxyl-valeric acid) acid amides
The title compound N of 500mg embodiment 1c, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3-oxygen base-valeric acid) acid amides use catalyzer (by the RuCl of 23.3mg
2(Ph)
2With the S-BiNAP of 62.6mg according to R.Selke, Angew.Chem.1998,110, method preparation p.1927-1930) carry out hydrogenation (under 40 ℃/100Bar 2 days).
Output: quantitatively
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?68.79 | ?9.02 |
| Measured value | ?69.00 | ?9.00 |
Embodiment 1e
N, N-dimethyl-3 (S)-(3,5-dihydroxyl-2,2-dimethyl-valeric acid) acid amides
Title compound N to 13.13g (47.70mmol) embodiment 1d, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (S)-hydroxyl-valeric acid) the Pearlman catalyzer (Pd on charcoal (OH) 2,20%) of interpolation 16g in the solution of acid amides in the 110ml tetrahydrofuran (THF).Hydrogenation is 7.5 hours under 10bar and room temperature.Filter out catalyzer, and vacuum-evaporation filtrate is to doing.
The colourless toughening oil of output: 8.63g (theoretical value 97%)
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?57.12 | ?10.12 | ?7.40 |
| Measured value | ?57.10 | ?10.00 | ?7.39 |
Embodiment 1f
N, N-dimethyl-(3 (S)-(3,5)-acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides
With the title compound N of 8.89g (47mmol) embodiment 1e, N-dimethyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) acid amides is dissolved in the acetone dimethyl ketone acetal of 27ml, adds camphor-10-sulfonic acid of 546mg then.Heated 15 hours to 50 ℃.Vacuum-evaporation is to doing, and residue is dissolved in the methylene dichloride of 200ml, with the saturated solution of sodium bicarbonate washing, washs with saturated nacl aqueous solution more then.Organic phase is dry on sodium sulfate, and vacuum-evaporation is to doing then.The oil of gained is leaving standstill crystallization down.
Output: 8.30g (theoretical value 77%) clear crystal
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?62.85 | ?10.11 | ?6.11 |
| Measured value | ?62.90 | ?10.00 | ?6.00 |
Embodiment 1g
N, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (S)-hydroxyl-valeric acid) acid amides
Under 0 ℃ with the N-tosyl group D-Xie Ansuan of 29.8g (0.11mmol) (document: J.Am.Chem.Soc.1937,59,116-118) be dissolved in the methylene dichloride of 100ml.Under 0 ℃, in 30 minutes time, drip the BH of 100ml
3-THF solution (1M) stirred 30 minutes then.Solution is cooled to-78 ℃.Under-78 ℃, add the solution of 16.42g (0.1mol) benzyloxy-propionic aldehyde in the 100ml methylene dichloride and the title compound N of 22.4g (0.12mol) embodiment 1a, N-dimethyl-(3 (S)-(3,5)-acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides, stirred 2 hours down at-78 ℃, be warmed under 0 ℃ the situation restir 2 hours then.
Add the Neutral ammonium fluoride of 5g and the methyl alcohol of 100ml, at room temperature stirred then 18 hours.The water that adds 150ml is hydrolyzed.With the ethyl acetate extraction of 200ml, organic phase is washed with 10% citric acid solution.After carry out chromatographically pure system with ethyl acetate/hexane as eluent on the silica gel, obtain the product (theoretical value 85%) of 24g.
Measure enantiomeric purity by HPLC, stationary phase is Chiracel AD 4.6 * 250mm, UV 208nm, eluent: hexane/isopropyl alcohol 99: 1, flow velocity: 1ml/min, t
R(S)=and 75min (97%), t
R(R)=79min (3%).
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?68.79 | ?9.02 |
| Measured value | ?68.65 | ?9.08 |
Be similar to embodiment 1e, 1f and 10 be converted into 2-(2, the 2-dimethyl-[1,3] diox-4-yl)-2-methyl-butane-3-ketone after, the enantiomeric purity of embodiment 10 compounds is increased to 99%ee (by crystallization in hexane, pentane or other hydrocarbon) after crystallization.
Embodiment 2
N, N-dimethyl-(3 (S)-3,5-two-t-butyldimethylsilyl oxygen base-2,2-dimethyl-valeric acid) acid amides
Title compound N to 3.96g (20.95mmol) embodiment 1e, N-dimethyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) adds the imidazoles of 7.31g (104.75mmol) and the tert-butyldimethylsilyl chloride of 7.9g (52.7mmol) in the solution of acid amides in the 20ml dimethyl formamide, at room temperature stirred then 16 hours.Solution is poured in the water of 200ml, and uses the hexanaphthene of 50ml to extract respectively 2 times.Organic phase merges, and vacuum-evaporation is to doing then.Residue carries out pure system (hexane/MTB ether) by flash chromatography on silica gel.
The colourless toughening oil of output: 8.31g (theoretical value 95%)
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?60.37 | ?11.34 | ?3.35 |
| Measured value | ?60.40 | ?11.36 | ?3.29 |
Embodiment 3
N, N-dimethyl-(3 (S)-3,5-hexanaphthene ketone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides
Title compound N to 3.96g (20.95mmol) embodiment 1e, N-dimethyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) tosic acid of interpolation 10mg in the solution of acid amides in 30.21g (0.2095mmol) pimelinketone-dimethyl ketone acetal stirred 6 hours down at 100 ℃ then.Solution is poured in the water of 200ml, and uses the hexanaphthene of 50ml to extract respectively 2 times.Organic phase merges, and vacuum-evaporation is to doing then.Residue carries out pure system (hexane/MTB ether) by flash chromatography on silica gel.
The colourless toughening oil of output: 5.08g (theoretical value 90%)
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?66.88 | ?10.10 | ?5.20 |
| Measured value | ?66.90 | ?10.20 | ?5.21 |
Embodiment 4
N, N-dimethyl-(3 (S)-3,5-phenyl aldehyde dimethylacetal-2,2-dimethyl-valeric acid) acid amides
The tosic acid of the phenyl aldehyde dimethylacetal of 31.9g (0.2095mmol) and 50mg is added into the title compound N of 3.96g (20.95mmol) embodiment 1e, N-dimethyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) in the solution of acid amides in the 20ml dimethyl formamide, stirred 6 hours down at 100 ℃ then.Solution is poured in the water of 200ml, uses the ethyl acetate extraction 2 times of 50ml then respectively.Merge organic phase, vacuum-evaporation is to doing then.Residue carries out pure system by flash chromatography (hexane/MTB ether) on silica gel.
The colourless toughening oil of output: 5.11g (theoretical value 88%)
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?69.29 | ?8.36 | ?5.05 |
| Measured value | ?69.30 | ?8.39 | ?5.00 |
Embodiment 5a
N, the N-dimethyl-(5-benzyloxy-2, and 2-dimethyl-3 (R, S)-acetoxyl group-valeric acid) acid amides
Under 0 ℃ to the title compound N of 30.65g (109.7mmol) embodiment 1b, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (R, S)-and hydroxyl-valeric acid) add the diacetyl oxide of 14.56g (142.64mmol) in the three second ammoniums of acid amides, 14.43g (142.64mmol) and the solution of 4-dimethylaminopyridine (DMAP) in 128ml MTB ether of 200mg, at room temperature stirred then 5 hours.Be poured in the frozen water of 2L, use the MTB ether of 300ml to extract then respectively 2 times.The MTB that merges washes with water 1 time to the 5% salt acid elution of 300ml 1 time again.Vacuum-evaporation is to doing.
Output: 33.50g (theoretical value 95%) water white oil
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?67.26 | ?8.47 | ?4.36 |
| Measured value | ?67.30 | ?8.50 | ?4.40 |
Embodiment 5b
N, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (S)-hydroxyl-valeric acid) acid amides
Title compound N with 11.67g (36.31mmol) embodiment 5a, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (R, S)-acetoxyl group-valeric acid) acid amides is added into-damping fluid in, this damping fluid is that the Sodium phosphate dibasic by the potassium primary phosphate of 0.88g and 1.82g makes in 250ml water.Add the lipase AYS " Amano " (relevant) of 5g, at room temperature stirred then 42.5 hours with Amano.Adding the Sodium phosphate dibasic of 2.062g, is 7 with pH regulator, and continues to stir 44.5 hours.Aftertreatment: the ethyl acetate extraction of usefulness 400ml 5 times.Organic phase merges, and vacuum-evaporation is to doing then.On silica gel, carry out pure system by chromatogram (hexane/ethyl acetate gradient).
Output: 4.60g (theoretical value 40%) water white oil
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?68.79 | ?9.02 | ?5.01 |
| Measured value | ?68.80 | ?9.00 | ?5.01 |
Embodiment 5c
N, N-dimethyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) acid amides
To the title compound N of 13.13g (47.70mmol) embodiment 5b, add the Pearlman catalyzer (Pd on charcoal (OH) of 16g in N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (S)-hydroxyl-valeric acid) acid amides solution in the 110ml tetrahydrofuran (THF)
2, 20%).Hydrogenation is 7.5 hours under 10bar and room temperature.Filter out catalyzer, and vacuum-evaporation filtrate is to doing.
The colourless toughening oil of output: 8.72g (theoretical value 98%)
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?57.12 | ?10.12 | ?7.40 |
| Measured value | ?57.10 | ?10.10 | ?7.39 |
Embodiment 5d
N, N-dimethyl-(3 (S)-(3,5)-acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides
With the title compound N of 6.62g (35.00mmol) embodiment 5c, N-dimethyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) acid amides is dissolved in the acetone dimethyl ketone acetal of 27ml, adds camphor-10-sulfonic acid of 546mg then.Heated 15 hours to 50 ℃.Vacuum-evaporation is to doing, and residue is dissolved in the methylene dichloride of 200ml, with the saturated solution of sodium bicarbonate washing, washs with saturated nacl aqueous solution more then.Organic phase is dry on sodium sulfate, and vacuum-evaporation is to doing then.The oil of gained is leaving standstill crystallization down.
Output: 5.93g (theoretical value 74%) clear crystal
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?62.85 | ?10.11 | ?6.11 |
| Measured value | ?62.90 | ?10.10 | ?6.10 |
Synthesizing of N-methyl-N-phenyl amide
Embodiment 6a
1-methyl isophthalic acid-phenyl amino-2-methyl isophthalic acid-trimethyl silyl-propylene
Under-35 ℃ and inert atmosphere, in the solution of 0.43mol diisopropylamine in 300ml THF, drip the butyllithium of 294ml (0.45ml).Then under 0 ℃, add N-methyl-N-phenyl-2 Methylpropionic acid acid amides of 76.92g (0.434mol), and under this temperature, stirred 30 minutes.Under-35 ℃, add the trimethylsilyl chloride of 60.3ml (0.47mol) then, and continue to stir 2 hours.In rotatory evaporator, distill solvent.Residue vacuum distilling under 65-69 ℃/30mbar.
Output: 70.36g (theoretical value 65%) oil
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?67.42 | ?9.29 |
| Measured value | ?67.50 | ?9.30 |
Embodiment 6b
N-methyl-N-phenyl-(5-benzyloxy-2,2-dimethyl-3-oxo-valeric acid) acid amides
In the THF of 500ml, stir 68.8g (0.367mol) 1-methyl isophthalic acid-phenyl-amino-2-methyl-1-trimethyl silyl-propylene, the 3-benzyloxy propionyl chloride of 81.06g (0.401mol) and the ZnCl of 5.56g
2Totally 1 hour.Add the NH of 13.88g
4The methyl alcohol of F and 300ml at room temperature stirred 18 hours then.Distillation removes and desolvates, residue 200ml ethyl acetate extraction, and organic phase is washed with 10% citric acid solution.After carry out chromatographically pure system with ethyl acetate/hexane as eluent on the silica gel, obtain the product (theoretical value 60%) of 74.74g.
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?74.31 | ?7.42 |
| Measured value | ?74.29 | ?7.40 |
Embodiment 6c
N-methyl-N-phenyl-(5-benzyloxy-2,2-dimethyl-3 (S)-hydroxyl-valeric acid) acid amides
Title compound N-methyl-N-phenyl of 500mg embodiment 6b-(5-benzyloxy-2,2-dimethyl-3-oxo-valeric acid) acid amides uses catalyzer (by the RuCl of 23.3mg
2(Ph)
2With the S-BiNAP of 62.6mg according to R.Selke, Angew.Chem.1998,110, method preparation p.1927-1930) carry out hydrogenation (under 40 ℃/100Bar 2 days).
Output: quantitatively
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?73.87 | ?7.97 |
| Measured value | ?74.00 | ?8.00 |
Embodiment 6d
N-methyl-N-phenyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) acid amides
In title compound N-methyl-N-phenyl-(5-benzyloxy-2,2-dimethyl-3 (S)-hydroxyl-valeric acid) acid amides solution in the 110ml tetrahydrofuran (THF) of 16.29g (47.70mmol) embodiment 6c, add the Pearlman catalyzer (Pd on charcoal (OH) of 16g
2, 20%).Hydrogenation is 7.5 hours under 10bar and room temperature.Filter out catalyzer, and vacuum-evaporation filtrate is to doing.
The colourless toughening oil of output: 11.98g (theoretical value 98%)
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?66.91 | ?8.42 | ?5.57 |
| Measured value | ?66.90 | ?8.40 | ?5.60 |
Embodiment 6e
N-methyl-N-phenyl-(3 (S)-(3,5)-acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides
Title compound N-methyl-N-phenyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) acid amides of 11.81g (47mmol) embodiment 6d is dissolved in the acetone dimethyl ketone acetal of 27ml, adds camphor-10-sulfonic acid of 546mg then.Heated 15 hours to 50 ℃.Vacuum-evaporation is to doing, and residue is dissolved in the methylene dichloride of 200ml, with the saturated solution of sodium bicarbonate washing, washs with saturated nacl aqueous solution more then.Organic phase is dry on sodium sulfate, and vacuum-evaporation is to doing then.The oil of gained is leaving standstill crystallization down.
Output: 10.54g (theoretical value 77%) clear crystal
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?70.07 | ?8.65 | ?4.81 |
| Measured value | ?70.00 | ?8.50 | ?4.90 |
Embodiment 7
N-methyl-N-phenyl-(3 (S)-3,5-pentamethylene ketone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides
Title compound N-methyl-N-phenyl-(3 (S)-3 to 5.26g (20.95mmol) embodiment 6d, 5-dihydroxyl-2,2-dimethyl-valeric acid) tosic acid of interpolation 10mg in the solution of acid amides in 30.21g (0.2095mmol) cyclopentanone-dimethyl ketone acetal stirred 6 hours down at 100 ℃ then.Solution is poured in the water of 200ml, and uses the ethyl acetate extraction 2 times of 50ml respectively.Organic phase merges, and vacuum-evaporation is to doing then.Residue carries out pure system (hexane/MTB ether) by flash chromatography on silica gel.
The colourless toughening oil of output: 5.98g (theoretical value 90%)
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?71.89 | ?8.57 | ?4.41 |
| Measured value | ?71.90 | ?8.60 | ?4.50 |
Embodiment 8
N-methyl-N-phenyl-(3 (S)-3,5-dichloro diphenyl silane-2,2-dimethyl-valeric acid) acid amides
Title compound N-methyl-N-phenyl-(3 (S)-3 to 5.26g (20.95mmol) embodiment 6d, 5-dihydroxyl-2,2-dimethyl-valeric acid) adds the imidazoles of 3.14g (46.09mmol) and the dichloro diphenyl silane of 5.83g (23.05mmol) in the solution of acid amides in the 20ml dimethyl formamide, at room temperature stirred then 16 hours.Solution is poured in the water of 200ml, and uses the dichloromethane extraction 2 times of 50ml respectively.Organic phase merges, and vacuum-evaporation is to doing then.Residue carries out pure system (hexane/MTB ether) by flash chromatography on silica gel.
The colourless toughening oil of output: 7.68g (theoretical value 85%)
Ultimate analysis:
| ?C | ?H | N | |
| Calculated value | ?72.35 | ?6.77 | ?3.25 |
| Measured value | ?72.37 | ?6.80 | ?3.30 |
Embodiment 9a
Racemize N, N-dimethyl-(3-hydroxyl-3-oxo-valeric acid) acid amides
2M LDA-THF solution with 13ml (26mmol) under-50 ℃ is added into 2.99g (26mmol) N, in N-dimethyl-2 Methylpropionic acid acid amides, stirs 30 minutes under this temperature then.Then add the propiolactone of 1.44g (20mmol), and continue to stir 20 hours being warmed under the situation of room temperature.With the saturated ammonium chloride solution washing, use ethyl acetate extraction.Under 1mbar after the drying, obtain the title compound (theoretical value 77%) of 2.8g embodiment 9a.
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?57.72 | ?9.15 | ?7.47 |
| Measured value | ?58.05 | ?8.95 | ?7.75 |
Embodiment 9b
N, N-dimethyl-3 (S)-(3,5-dihydroxyl-2,2-dimethyl-valeric acid) acid amides
1.87g (10mmol) the title compound racemize N of embodiment 1c, N-dimethyl-(3-hydroxyl-3-oxo-valeric acid) acid amides use catalyzer (by the RuCl of 75mg
2(Ph)
2With the S-BiNAP of 190mg according to R.Selke, Angew.Chem.1998,110, method preparation p.1927-1930) carry out hydrogenation (under 40 ℃/100Bar 2 days).
Output: quantitatively
Ultimate analysis:
| ?C | ?H | ?N | |
| Calculated value | ?57.11 | ?10.1 | ?7.4 |
| Measured value | ?57.60 | ?10.3 | ?7.7 |
Embodiment 10
(S)-3-(2, the 2-dimethyl-[1,3] diox-4-yl)-3-methyl-butane-2-ketone
Under-20 ℃, lithium methide-lithiumbromide mixture (diethyl ether solution of 1.5M) of 35.6ml is dropped to the title compound N of 4.08g (17.79mmol) embodiment 1f, N-dimethyl-(3 (S)-(3,5)-and acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) in the solution of acid amides in the 5ml ether.Stirred 30 minutes down at-20 ℃, be heated to room temperature then.At room temperature stir and spend the night.Add the saturated ammonium chloride solution of 10ml, and at room temperature stirred 6 hours.Separate organic phase, and wash with water 2 times.The vacuum-evaporation organic phase is to doing.Residue carries out chromatographically pure system (hexane/ethyl acetate gradient) on silica gel.
Output: 2.77g (theoretical value 78%) oil
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?65.97 | ?10.07 |
| Measured value | ?65.84 | ?10.19 |
Embodiment 11
(S)-2-(2, the 2-dimethyl-[1,3] diox-4-yl)-2-methyl-heptane-3-ketone
Under-65 ℃ with the n-Butyl Lithium (15% of 34ml, 1.6M hexane solution) drop to the title compound N of 4.08g (17.79mmol) embodiment 1f, in N-dimethyl-(3 (S)-(3,5)-acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides solution in 5ml THF.Stirred 30 minutes down at-65 ℃, be heated to room temperature then.At room temperature stir and spend the night.Add the saturated ammonium chloride solution of 10ml, and at room temperature stirred 6 hours.Separate organic phase, and wash with water 2 times.Vacuum-evaporation concentrates organic phase.Residue carries out chromatographically pure system (hexane/ethyl acetate gradient) on silica gel.
Output: 4.13g (theoretical value 96%) oil
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?69.38 | ?10.81 |
| Measured value | ?69.27 | ?10.96 |
Embodiment 12
(4S)-and 4-(2-methyl-3-oxo-heptan-6-alkene-2-yl)-2,2-dimethyl-(1,3) diox
Under-90 ℃, the 3-butenyl lithium solution of 50ml (is rolled up No. 21 according to J.Org.Chem. the 56th, 6094-6103 page or leaf (1991) or J.Chem.Soc.Perkin Trans.1pp.2937 (1988) are made by 4-bromo-1-butylene and lithium silk or tert-butyl lithium) drop to the title compound N of 4.08g (17.79mmol) embodiment 1f, N-dimethyl-(3 (S)-(3,5)-and acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) in the solution of acid amides in the 5ml ether.Stirred 17 hours down at-90 ℃, be heated to room temperature then.At room temperature stir and spent the night totally 17 hours.Add the saturated ammonium chloride solution of 10ml, and at room temperature stirred 6 hours.Separate organic phase, and wash with water 2 times.The vacuum-evaporation organic phase is to doing.Residue carries out chromatographically pure system (hexane/ethyl acetate gradient) on silica gel.
Output: 2.74g (theoretical value 70%) oil
Ultimate analysis:
| ?C | ?H | |
| Calculated value | ?69.96 | ?10.06 |
| Measured value | ?69.90 | ?10.05 |
Embodiment 13
N, N-dimethyl-2,2-dimethyl-pentane-1,5-dioctyl phthalate-1-acid amides-5-ethyl ester
At the propanedioic acid list ethyl ester muriate that in 1g (5.35mmol) 1-dimethylamino-solution of 2-methyl isophthalic acid-trimethyl silyl-propylene in 3ml THF, adds 0.81g (5.35mmol) under 0 ℃, the Zinc Chloride Anhydrous that adds 72mg stirred 2 hours at 0 ℃ then as catalyzer.Be added in the water of 10ml, use the ethyl acetate extraction 2 times of 10ml respectively, on silica gel, carry out chromatographically pure system then.Output is 0.958g (theoretical value 77%).
MS-Cl/NH
3(70eV)，M/Z＝230[M-H]
+
1H-NMR(300MHz，CDCl3，25℃，TMS)，δ＝01.4(s，6H)，2.9(m，6H)，3.48(s，2H)，4.25(m，4H)
The abbreviation of used ether protecting group
The TES=triethylsilyl
The TMS=trimethyl silyl
The TIP=triisopropyl
The TBDPS=t-butyldimethylsilyl
MEM=methyl ethoxy methyl
The MOM=methoxymethyl
THP=THP trtrahydropyranyl (ether)
Claims (31)
1, the compound of general formula I:
R wherein
1, R
2Can be identical or different, and represent pure protecting group independently of each other, as benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl group, trityl,
If perhaps R
1And R
2Bridge joint is then represented the ketone acetal protecting group together:
U wherein
1, U
2Represent alkyl, phenyl, the tertiary butyl, U represents C
1-6Alkyl;
Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
2, the compound of general formula I a:
R wherein
1, R
2Can be identical or different, and represent pure protecting group independently of each other, as benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl group, trityl,
If perhaps R
1And R
2Bridge joint is then represented the ketone acetal protecting group together:
U wherein
1, U
2Represent alkyl, phenyl, the tertiary butyl, U represents C
1-6Alkyl;
Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
3, the compound of general formula I b:
R wherein
1, R
2Can be identical or different, and represent pure protecting group independently of each other, as benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl group, trityl,
If perhaps R
1And R
2Bridge joint is then represented the ketone acetal protecting group together:
U wherein
1, U
2Represent alkyl, phenyl, the tertiary butyl, U represents C
1-6Alkyl;
Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
4, the compound of general formula I I:
Wherein Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
5, compound as claimed in claim 4, wherein secondary alcohol carbon atom place is configured as S.
6, compound as claimed in claim 4, wherein secondary alcohol carbon atom place is configured as R.
7, the compound of general formula III:
R wherein
1Represent pure protecting group, as benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl group, trityl, and
Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
8, compound as claimed in claim 7, wherein secondary alcohol carbon atom place is configured as S.
9, compound as claimed in claim 7, wherein secondary alcohol carbon atom place is configured as R.
10, the compound of general formula X II:
R wherein
4Represent C
1-6Alkyl, methyl, ethyl, the tertiary butyl, phenyl or benzyl, and Y represents group-NA1A2, wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
11, compound as claimed in claim 10, wherein secondary alcohol carbon atom place is configured as R.
12, as the described general formula I of one of claim 1-11, Ia, Ib, II, III, the application of XII compound in synthesis of natural and synthetic esperamicin.
13, preparation is as the method for one of claim 1-3 described compound, wherein by claim 4-6 it-compound as initiator, alcohol radical protecting group R
1And R
2Protection.
14, method as claimed in claim 13, wherein protecting group R
1And R
2Represent acetone ketone acetal and TBDMS group.
15, the method for the optically-active compound of preparation general formula III a:
It comprises the racemate by enzyme reaction method enantio-selectivity ground saponification general formula VI
R wherein
1Represent pure protecting group, as benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl group, trityl,
Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
R
3Represent C
1-6Alkyl or allyl group, phenyl or benzyl.
16, method as claimed in claim 15, wherein the used enzyme of saponification reaction is lipase Amano AY.
17, the method for the optically-active compound of preparation general formula III a:
R wherein
1Represent pure protecting group, as benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl group, trityl,
Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
This method comprises by the compound of general formula VII initial, carries out chiral reduction:
Wherein R1 is identical with above definition with Y.
18, method as claimed in claim 17, wherein the chiral reduction of ketone group is undertaken by catalytic hydrogenation with Noyori type catalyzer.
19, method as claimed in claim 17, wherein the chiral reduction of ketone group is undertaken by enzymatic reduction.
20, the method for the compound of preparation general formula X III
R wherein
4Represent C
1-6Alkyl, methyl, ethyl, the tertiary butyl, phenyl or benzyl, Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
This method comprises the compound that makes general formula X IV
R wherein
4Represent C
1-6Alkyl, methyl, ethyl, the tertiary butyl, phenyl or benzyl, Nu represents leavings group, as Cl, Br, imidazoles ,-OPh ,-O-C
6H
4NO
2,-O-C
1-4Alkyl,
Compound reaction with formula V
Wherein L represents the silyl protecting group, and
Y represents group-NA1A2, and wherein A1 and A2 represent C independently of each other
1-6Alkyl, as methyl, ethyl, propyl group, perhaps aryl or aralkyl, as phenyl, benzyl, OH, OMe, O-benzyl, the perhaps following group of representative:
21, N, N-dimethyl-(3 (S)-(3,5)-acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides:
22, N, N-dimethyl-(3 (S)-3,5 phenyl aldehyde dimethylacetals-2,2-dimethyl-valeric acid) acid amides:
23, N, N-dimethyl-(3 (S)-3,5-two-t-butyldimethylsilyl oxygen base-2,2-dimethyl-valeric acid) acid amides:
24, N, N-dimethyl-(3 (S)-3,5-hexanaphthene ketone-dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides:
25, N-methyl-N-phenyl-(3 (S)-(3,5)-acetone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides:
26, N-methyl-N-phenyl-(3 (S)-3,5-pentamethylene ketone dimethyl ketone acetal-2,2-dimethyl-valeric acid) acid amides:
27, N-methyl-N-phenyl-(3 (S)-3,5-diphenyl silane oxygen base-2,2-dimethyl-valeric acid) acid amides:
28, N, N-dimethyl-(3 (S)-3,5-dihydroxyl-2,2-dimethyl-valeric acid) acid amides:
29, N, N-dimethyl-(5-benzyloxy-2,2-dimethyl-3 (S)-hydroxyl-valeric acid) acid amides:
30, the method for the ketone of preparation general formula A
R wherein
1, R
2Can be identical or different, and represent pure protecting group independently of each other, as benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, allyl group, trityl,
If perhaps R
1And R
2Bridge joint is then represented the ketone acetal protecting group together:
U wherein
1, U
2Represent alkyl, phenyl, the tertiary butyl, U represents C
1-6Alkyl, V represents C
1-5Alkyl or alkenyl,
This method comprises the compound that makes general formula I a
Compound reaction with Formula B
M-V????????????(B)
Wherein M represents Li or MgCl, MgBr or MgI,
Under hydrolysising condition, carry out aftertreatment then.
31, method as claimed in claim 30, wherein preferably MeLi, EtLi, propyl lithium, BuLi, CH of the compound of formula M-V
2=CH-CH
2CH
2-Li.
32, compound of Formula I as claimed in claim 1 or general formula I a compound as claimed in claim 2 or general formula I b compound as claimed in claim 3 or general formula I I compound as claimed in claim 4 or compound of formula III as claimed in claim 7 or general formula X II compound as claimed in claim 10 application in preparation esperamicin or esperamicin derivatives.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10138348A DE10138348A1 (en) | 2001-08-03 | 2001-08-03 | Protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and methods of preparation and use |
| DE10138348.7 | 2001-08-03 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100764590A Division CN1807403A (en) | 2001-08-03 | 2002-08-05 | Protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and process for the production and the use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1538952A true CN1538952A (en) | 2004-10-20 |
Family
ID=7694415
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100764590A Pending CN1807403A (en) | 2001-08-03 | 2002-08-05 | Protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and process for the production and the use |
| CNA028152379A Pending CN1538952A (en) | 2001-08-03 | 2002-08-05 | Protected 3,5-dihydroxy-2, 2-dimethyl-valeroamides for synthesis of epothilone and derivatives and method for production and use thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100764590A Pending CN1807403A (en) | 2001-08-03 | 2002-08-05 | Protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and process for the production and the use |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP1412322A2 (en) |
| JP (1) | JP2004537589A (en) |
| KR (1) | KR20040029394A (en) |
| CN (2) | CN1807403A (en) |
| AR (1) | AR036207A1 (en) |
| BR (1) | BR0211649A (en) |
| CA (1) | CA2456255A1 (en) |
| DE (1) | DE10138348A1 (en) |
| IL (1) | IL160159A0 (en) |
| MX (1) | MXPA04000954A (en) |
| NO (1) | NO20040912L (en) |
| PE (1) | PE20030345A1 (en) |
| PL (1) | PL367430A1 (en) |
| RU (1) | RU2004106530A (en) |
| WO (1) | WO2003014063A2 (en) |
| ZA (1) | ZA200401727B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110857276A (en) * | 2018-08-22 | 2020-03-03 | 中国科学院化学研究所 | A class of chiral β-hydroxyamide compounds, preparation method and application thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1386922B1 (en) | 1996-12-03 | 2012-04-11 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereof, analogues and uses thereof |
| US6867305B2 (en) | 1996-12-03 | 2005-03-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| WO2003029195A1 (en) | 2001-09-28 | 2003-04-10 | Sumika Fine Chemicals Co., Ltd. | Intermediates for epothilone derivative and process for producing these |
| DE10326195A1 (en) * | 2003-06-07 | 2004-12-23 | Schering Ag | Protected 5,7-dihydroxy-4,4-dimethyl-3-oxoheptanoic acid esters and 5,7-dihydroxy-2-alkyl-4,4-dimethyl-3-oxoheptanoic acid esters for the synthesis of epothilones and derivatives and processes for the preparation of these esters |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4824980A (en) * | 1988-09-02 | 1989-04-25 | Dow Corning Corporation | Process to produce O-silyl O,N-ketene acetals |
| US6211412B1 (en) * | 1999-03-29 | 2001-04-03 | The University Of Kansas | Synthesis of epothilones |
-
2001
- 2001-08-03 DE DE10138348A patent/DE10138348A1/en not_active Withdrawn
-
2002
- 2002-08-02 AR ARP020102940A patent/AR036207A1/en unknown
- 2002-08-02 PE PE2002000704A patent/PE20030345A1/en not_active Application Discontinuation
- 2002-08-05 BR BR0211649-9A patent/BR0211649A/en not_active IP Right Cessation
- 2002-08-05 EP EP02774500A patent/EP1412322A2/en not_active Withdrawn
- 2002-08-05 JP JP2003519015A patent/JP2004537589A/en active Pending
- 2002-08-05 MX MXPA04000954A patent/MXPA04000954A/en unknown
- 2002-08-05 PL PL02367430A patent/PL367430A1/en unknown
- 2002-08-05 CA CA002456255A patent/CA2456255A1/en not_active Abandoned
- 2002-08-05 RU RU2004106530/04A patent/RU2004106530A/en not_active Application Discontinuation
- 2002-08-05 KR KR10-2004-7001710A patent/KR20040029394A/en not_active Application Discontinuation
- 2002-08-05 CN CNA2005100764590A patent/CN1807403A/en active Pending
- 2002-08-05 CN CNA028152379A patent/CN1538952A/en active Pending
- 2002-08-05 IL IL16015902A patent/IL160159A0/en unknown
- 2002-08-05 WO PCT/EP2002/008726 patent/WO2003014063A2/en active Application Filing
-
2004
- 2004-03-02 ZA ZA200401727A patent/ZA200401727B/en unknown
- 2004-03-02 NO NO20040912A patent/NO20040912L/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110857276A (en) * | 2018-08-22 | 2020-03-03 | 中国科学院化学研究所 | A class of chiral β-hydroxyamide compounds, preparation method and application thereof |
| CN110857276B (en) * | 2018-08-22 | 2021-03-02 | 中国科学院化学研究所 | A class of chiral β-hydroxyamide compounds, preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2456255A1 (en) | 2003-02-20 |
| EP1412322A2 (en) | 2004-04-28 |
| DE10138348A1 (en) | 2003-02-27 |
| BR0211649A (en) | 2004-07-13 |
| JP2004537589A (en) | 2004-12-16 |
| MXPA04000954A (en) | 2004-04-20 |
| AR036207A1 (en) | 2004-08-18 |
| WO2003014063A2 (en) | 2003-02-20 |
| CN1807403A (en) | 2006-07-26 |
| KR20040029394A (en) | 2004-04-06 |
| NO20040912L (en) | 2004-03-02 |
| PL367430A1 (en) | 2005-02-21 |
| IL160159A0 (en) | 2004-07-25 |
| ZA200401727B (en) | 2005-04-12 |
| PE20030345A1 (en) | 2003-04-10 |
| RU2004106530A (en) | 2005-07-27 |
| WO2003014063A3 (en) | 2003-05-01 |
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